{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:29:21Z","timestamp":1788866961533,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T00:00:00Z","timestamp":1665360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, USA","award":["R01 HL144125"],"award-info":[{"award-number":["R01 HL144125"]}]},{"name":"National Institutes of Health, USA","award":["R01 HL147662"],"award-info":[{"award-number":["R01 HL147662"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated by innate and adaptive immune response involving infiltration of immune cells and secretion of pro- and anti-inflammatory cytokines. Impaired immune cell infiltration and change in vascular smooth muscle cell (VSMC) phenotype play a crucial role in the underlying pathophysiology. However, the change in the phenotype of VSMCs in a microenvironment of immune cell infiltration and increased secretion of cytokines have not been investigated. Since change in VSMC phenotype regulates vessel remodeling after intimal injury, in this study, we investigated the effect of macrophages and pro-inflammatory cytokines, IL-6, IL-1\u03b2, and TNF-\u03b1, on the change in VSMC phenotype under in vitro conditions. We also investigated the expression of the markers of VSMC phenotypes in arteries with atherosclerotic plaques and VSMCs isolated from control arteries. We found that the inhibition of cytokine downstream signaling may mitigate the effect of cytokines on the change in VSMCs phenotype. The results of this study support that regulating or targeting immune cell infiltration and function might be a therapeutic strategy to mitigate the effects of chronic inflammation to attenuate plaque formation, early thrombosis, and stenosis, and thus enhance AVF maturation.<\/jats:p>","DOI":"10.3390\/ijms231912012","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T01:21:07Z","timestamp":1665364867000},"page":"12012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Targeting the Crosstalk of Immune Response and Vascular Smooth Muscle Cells Phenotype Switch for Arteriovenous Fistula Maturation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-2341","authenticated-orcid":false,"given":"Vikrant","family":"Rai","sequence":"first","affiliation":[{"name":"Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harbinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-0013","authenticated-orcid":false,"given":"Devendra K.","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1139\/cjpp-2016-0664","article-title":"The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques","volume":"95","author":"Rai","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.ecl.2017.07.009","article-title":"Role of Vitamin D in Cardiovascular Diseases","volume":"46","author":"Rai","year":"2017","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.dib.2016.05.047","article-title":"Data on TREM-1 activation destabilizing carotid plaques","volume":"8","author":"Rao","year":"2016","journal-title":"Data Brief"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Rai, V., Rao, V.H., Shao, Z., and Agrawal, D.K. (2016). Dendritic Cells Expressing Triggering Receptor Expressed on Myeloid Cells-1 Correlate with Plaque Stability in Symptomatic and Asymptomatic Patients with Carotid Stenosis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154802"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.atherosclerosis.2016.03.021","article-title":"Tumor necrosis factor-alpha regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosis","volume":"248","author":"Rao","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rai, V., and Agrawal, D.K. (2017). Pathogenesis of the plaque vulnerability in diabetes mellitus. Mechanisms of Vascular Defects in Diabetes Mellitus, Springer.","DOI":"10.1007\/978-3-319-60324-7_4"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"H1075","DOI":"10.1152\/ajpheart.00378.2015","article-title":"Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells","volume":"309","author":"Rao","year":"2015","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/nm1459","article-title":"Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis","volume":"12","author":"Clarke","year":"2006","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1093\/cvr\/cvy022","article-title":"Smooth muscle cell fate and plasticity in atherosclerosis","volume":"114","author":"Allahverdian","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.3389\/fphar.2019.01276","article-title":"Immune and Smooth Muscle Cells Interactions in Atherosclerosis: How to Target a Breaking Bad Dialogue?","volume":"10","author":"Ramel","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1161\/CIRCRESAHA.115.306361","article-title":"Vascular Smooth Muscle Cells in Atherosclerosis","volume":"118","author":"Bennett","year":"2016","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1161\/CIRCULATIONAHA.115.016457","article-title":"Vascular Smooth Muscle Cell Senescence Promotes Atherosclerosis and Features of Plaque Vulnerability","volume":"132","author":"Wang","year":"2015","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Goikuria, H., Freijo, M.D.M., Vega Manrique, R., Sastre, M., Elizagaray, E., Lorenzo, A., Vandenbroeck, K., and Alloza, I. (2018). Characterization of Carotid Smooth Muscle Cells during Phenotypic Transition. Cells, 7.","DOI":"10.3390\/cells7030023"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1093\/cvr\/cvab046","article-title":"Vascular smooth muscle cells in atherosclerosis: Time for a re-assessment","volume":"117","author":"Grootaert","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.3389\/fimmu.2019.01101","article-title":"Vascular Smooth Muscle Cells Contribute to Atherosclerosis Immunity","volume":"10","author":"Hu","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"599415","DOI":"10.3389\/fimmu.2020.599415","article-title":"Role of Vascular Smooth Muscle Cell Plasticity and Interactions in Vessel Wall Inflammation","volume":"11","author":"Sorokin","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3741","DOI":"10.1111\/bph.14779","article-title":"The role of smooth muscle cells in plaque stability: Therapeutic targeting potential","volume":"176","author":"Harman","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1161\/ATVBAHA.121.316233","article-title":"Crosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability","volume":"42","author":"Yurdagul","year":"2022","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bonetti, J., Corti, A., Lerouge, L., Pompella, A., and Gaucher, C. (2021). Phenotypic Modulation of Macrophages and Vascular Smooth Muscle Cells in Atherosclerosis-Nitro-Redox Interconnections. Antioxidants, 10.","DOI":"10.3390\/antiox10040516"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1152\/physiolgenomics.00160.2011","article-title":"Interleukin-1beta modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-kappaB-dependent mechanisms","volume":"44","author":"Alexander","year":"2012","journal-title":"Physiol. Genom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"679797","DOI":"10.3389\/fmolb.2021.679797","article-title":"Macrophage Plasticity and Atherosclerosis Therapy","volume":"8","author":"Lin","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rai, V., and Agrawal, D.K. (2022). Transcriptional and Epigenetic Factors Associated with Early Thrombosis of Femoral Artery Involved in Arteriovenous Fistula. Proteomes, 10.","DOI":"10.3390\/proteomes10020014"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rai, V., and Agrawal, D.K. (2022). Transcriptomic Analysis Identifies Differentially Expressed Genes Associated with Vascular Cuffing and Chronic Inflammation Mediating Early Thrombosis in Arteriovenous Fistula. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020433"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"432","DOI":"10.26502\/fccm.92920280","article-title":"TLR-4 Inhibition Attenuates Inflammation, Thrombosis, and Stenosis in Arteriovenous Fistula in Yucatan Miniswine","volume":"6","author":"Rai","year":"2022","journal-title":"Cardiol. Cardiovasc. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12950-020-00267-z","article-title":"Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells","volume":"18","author":"Kohno","year":"2021","journal-title":"J. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1139\/cjpp-2021-0731","article-title":"Innate and Adaptive Immune Cells Associates with Arteriovenous Fistula Maturation and Failure","volume":"100","author":"Samra","year":"2022","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"423","DOI":"10.26502\/jsr.10020237","article-title":"Heterogeneous Population of Immune cells Associated with Early Thrombosis in Arteriovenous Fistula","volume":"5","author":"Samra","year":"2022","journal-title":"J. Surg. Res."},{"key":"ref_28","unstructured":"Davarinejad, H. (2015). Quantifications of Western Blots with ImageJ, University of York."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"110794","DOI":"10.1016\/j.jtbi.2021.110794","article-title":"Role of vascular smooth muscle cell phenotypic switching in plaque progression: A hybrid modeling study","volume":"526","author":"Pan","year":"2021","journal-title":"J. Theor. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16314","DOI":"10.1074\/jbc.RA120.015486","article-title":"TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells","volume":"295","author":"Zhao","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e22","DOI":"10.1016\/j.atherosclerosis.2020.10.080","article-title":"Repression of MAP1LC3A during atherosclerosis progression plays an important role in the regulation of vascular smooth muscle cell phenotype","volume":"315","author":"Ehrenborg","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s44161-022-00042-8","article-title":"Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque","volume":"1","author":"Cheng","year":"2022","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13287-018-0876-3","article-title":"Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro","volume":"9","author":"Yang","year":"2018","journal-title":"Stem. Cell Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.3892\/mmr.2017.6106","article-title":"TNFalpha regulates apoptosis of human vascular smooth muscle cells through gap junctions","volume":"15","author":"Tang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1177\/1358863X14550542","article-title":"Design and utilization of macrophage and vascular smooth muscle cell co-culture systems in atherosclerotic cardiovascular disease investigation","volume":"19","author":"Zuniga","year":"2014","journal-title":"Vasc. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"719456","DOI":"10.3389\/fgene.2021.719456","article-title":"Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotype Switching in Atherosclerotic Artery Remodeling: A Mini-Review","volume":"12","author":"Zurek","year":"2021","journal-title":"Front. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.bbagrm.2014.06.004","article-title":"Epigenetic regulation of smooth muscle cell plasticity","volume":"1849","author":"Liu","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20130852","DOI":"10.1098\/rsif.2013.0852","article-title":"Biomechanical regulation of vascular smooth muscle cell functions: From in vitro to in vivo understanding","volume":"11","author":"Qiu","year":"2014","journal-title":"J. R. Soc. Interface"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"37","DOI":"10.4196\/kjpp.2017.21.1.37","article-title":"Regulation of vascular smooth muscle phenotype by cross-regulation of kruppel-like factors","volume":"21","author":"Ha","year":"2017","journal-title":"Korean J. Physiol. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1161\/hh1501.094265","article-title":"Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids","volume":"89","author":"Hayashi","year":"2001","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Garbuzova-Davis, S., Ehrhart, J., Sanberg, P.R., and Borlongan, C.V. (2018). Potential Role of Humoral IL-6 Cytokine in Mediating Pro-Inflammatory Endothelial Cell Response in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020423"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/s12276-021-00649-0","article-title":"Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms","volume":"53","author":"Kang","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fphar.2017.00363","article-title":"IL-1beta Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus","volume":"8","author":"Peiro","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"589654","DOI":"10.3389\/fimmu.2020.589654","article-title":"Targeting IL-1beta in the Treatment of Atherosclerosis","volume":"11","author":"Mai","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_45","first-page":"9","article-title":"TNF-\u03b1 in the cardiovascular system: From physiology to therapy","volume":"7","author":"Urschel","year":"2015","journal-title":"Int. J. Interferon Cytokine Mediat. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Rolski, F., and Blyszczuk, P. (2020). Complexity of TNF-alpha Signaling in Heart Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9103267"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41392-022-00955-7","article-title":"Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention","volume":"7","author":"Kong","year":"2022","journal-title":"Signal Transduct. Target"},{"key":"ref_48","first-page":"1358","article-title":"The Role of Cytokines in the Development of Atherosclerosis","volume":"81","author":"Fatkhullina","year":"2016","journal-title":"Biochemistry"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Poznyak, A.V., Bharadwaj, D., Prasad, G., Grechko, A.V., Sazonova, M.A., and Orekhov, A.N. (2021). Anti-Inflammatory Therapy for Atherosclerosis: Focusing on Cytokines. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137061"},{"key":"ref_50","first-page":"A415","article-title":"Resolvin D1 Favorably Impacts Arteriovenous Fistula Healing and Maturation in Mice with Chronic Kidney Disease","volume":"39","author":"Cui","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1080\/14779072.2019.1612745","article-title":"Pro-inflammatory and pro-resolving mechanisms in the immunopathology of arteriovenous fistula maturation","volume":"17","author":"Satish","year":"2019","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"188S","DOI":"10.1016\/j.jvs.2018.05.206","article-title":"Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model","volume":"68","author":"Wu","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.stemcr.2019.05.003","article-title":"Differentiation and Functional Comparison of Monocytes and Macrophages from hiPSCs with Peripheral Blood Derivatives","volume":"12","author":"Cao","year":"2019","journal-title":"Stem. Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/12012\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:00Z","timestamp":1760143740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/12012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,10]]},"references-count":53,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231912012"],"URL":"https:\/\/doi.org\/10.3390\/ijms231912012","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,10]]}}}